The Type 5 adenylyl cyclase (AC-5) isoform is expressed in several organs, but is a predominant isoform in the heart. To study the role of AC-5 regulation, we generated a genetically engineered mouse model in which the expression of AC-5 is knocked out (AC-5 KO). Our initial studies demonstrated a protective role in response to either chronic pressure-overload or chronic catecholamine stress in the heart in the AC-5 KO mice. Recently, we observed that our AC-5 KO mice live longer than WT mice and do not exhibit the adverse effects of aging on the heart and on osteoporosis. Our finding supports the concept that AC-5 plays a major role in the regulation of the aging process. However, the mechanism for increased longevity in AC-5 mice is completely unknown. Our preliminary studies have demonstrated that AC-5 KO mice are resistant to apoptosis and oxidative stress. By using proteomic approaches we found that the Raf/MEK/ERK signaling pathway, which controls cell growth and survival, mediated by cAMP and AC, is activated in AC-5 KO mice. Raf/MEK/ERK is one of major signaling pathways activated in response to oxidative stress and apoptosis. Therefore, the main hypotheses of this proposal are: (A) Knocking out AC-5 enhances cellular resistance to oxidative stress through the activation of ERK and its downstream target superoxide dismutase (SOD), which results in extended life span. (B) Knocking out AC-5 protects against oxidative and DMA damage from reactive oxygen species (ROS) produced by energy metabolism, a key mechanism of aging process. The deletion of AC-5 decreases the mitochondrial ROS production and oxidative DNA damage. (C) Knocking out AC-5 further evokes anti-apoptotic and cell survival mechanism(s) through the activation of ERK, which lead to AC-5 KO mice against aging, pressure overload and myocardial ischemia. These studies will lead to an elucidation of molecular mechanisms of longevity in AC-5 KO mice and further provide insights into cellular and molecular mechanisms of anti-aging. This proposal has major implications for public health. The disability associated with aging has a major impact on the public health and the economy of this country. Finding molecular switches, such as the one described in this project, could ameliorate disability with aging and would be a major step forward. [unreadable] [unreadable] [unreadable]